Our overarching goal is to further resolve the neurodegenerative role of traffic-related air pollutants (TRAP), a ubiquitous exposure in urban areas where most older Americans reside. Our recently published epidemiologic data showed strong association between elevated PM2.5 (particulate matter <2.5m) and increased dementia risk in women >65 years, with a bias for ApoE4 homozygotes (JC Chen in Cacciottolo et al 2017, PMID 28140404). In this same report, experimental studies of female mice from the Finch-Sioutas Labs showed that exposure to nPM (a nano-sized subfraction of TRAP) was pro-amyloidogenic with an ApoE4 bias. Other changes include attrition of hippocampal CA1 neurites and myelin, which model selective damage in AD and cerebral ischemia. In a mouse stroke model, nPM exposure exacerbated cerebral ischemic damage (William Mack: Liu et al 2016, PMID 27071057). Differences by sex and ApoE alleles suggest sources of heterogeneity in human responses to TRAP. We propose four projects: epidemiological studies of two nationwide cohorts of women (Project 1, JC Chen: Women's Health Initiative Memory Studies; WHIMS) and men (Project 2, C Franz and W Kremen: Vietnam Era Twin Study of Aging, VETSA) and two experimental studies of air pollution exposure (Project 3, Finch: mouse models of aging and AD; Project 4 Wm Mack, chronic ceebral hypoperfusion). These projects address a common set of questions: (1) What is the AD risk imposed by TRAP and does the associated risk vary by sex, life stage, and APOE/other alleles? (2) What neurodegenerative changes are induced by TRAP and what is the resulting risk for early cognitive decline of AD? (3) Which brain pathways are most susceptible to TRAP neurotoxicity? (4) Do shared mechanisms (e.g., amyloidogenesis, cerebrovascular damage and hypoperfusion, and neuroinflammation) predispose to premature cognitive decline and an increased AD risk? Two supporting Cores provide population neuroinformatics, neuroimaging of blood-brain-barrier (BBB) and myelinated tracts, large-scale air pollution modeling and epidemiology, inhalation exposure assessment and neurotoxicology. Neuroimaging Core B1 provides human brain imaging harmonized across sites and mediation analyses (Projects1-2). B2 provides high-resolution imaging of BBB and tractography for mouse models (Projects 3-4). Core C Environmental Exposure and Neurotoxicology subcore C1 harmonizes population exposure estimates for WHIMS and VETSA (Projects1-2); C2 provides inhalation exposure of mice for studies of sex and ApoE allele responses (Project 3) and of chronic cerebral hypoperfusion (Project 4); C3 analyzes brain inflammatory protein responses to TRAP. For P01 integration, the Administrative Core builds on the infrastructure of AirPollBrain (led by Finch& Chen), a USC-funded collaborative network since 2010. Results of this program will advance understanding of TRAP contributions to AD risk and accelerated cognitive decline, and provide a rationale for preventive intervention in the environmental neurotoxicology of AD.